Project Summary/Abstract COPD is projected to become the third most common cause of death worldwide, and we currently lack any medical therapies that significantly alter the course of this disease. Our recent work identifies ADAM9 (a disintegin and metalloproteinase domain) as the first proteinase that promotes the three key COPD pulmonary pathologies (emphysema, small airway fibrosis, and airway mucus cell metaplasia) in cigarette smoke-exposed mice. Moreover, ADAM9 expression is robustly increased in lung epithelial cells and macrophages in the lungs of COPD patients, even in early-stage disease. Additionally, Adam9 mediates its activities, in part, by increasing lung inflammation, degrading lung elastin, and shedding epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) to reduce the survival of alveolar septal cells, and increase the number of activated small airway myofibroblasts. We have developed a protein therapeutic based on a domain of ADAM9 that specifically targets this enzyme's activity to reduce shedding of a number of substrates for ADAM9. We have promising results using this protein in mice acutely exposed to smoke. In Aim 1 we will establish the pharmacokinetics, maximum tolerated dose and dosing regimen for use in the efficacy study. Aim 2 will focus on performing a proof-of-concept six-month cigarette-smoke exposure experiment that will serve to demonstrate satisfactory efficacy of our inhibitor. Successful completion of the aims will advance this protein therapeutic towards the clinic as the first disease-modifying therapy for COPD, with potential to slow the progression of key COPD phenotypes associated with lung function impairment, morbidity and mortality.